Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential.
Significant advances have been made in understanding the underlying defects of and developing potential treatments for Fragile X syndrome (FXS), the most common heritable mental retardation. It has been shown that neuronal metabotropic glutamate receptor 5 (mGluR5)-mediated signaling is affected in FX animal models, with consequent alterations in activity-dependent protein translation and synaptic spine functionality. We demonstrate here that a central metabolic regulatory enzyme, glycogen synthase kinase-3 (GSK3) is present in a form indicating elevated activity in several regions of the FX mouse brain. Furthermore, we show that selective GSK3 inhibitors, as well as lithium, are able to revert mutant phenotypes of the FX mouse. Lithium, in particular, remained effective with chronic administration, although its effects were reversible even when given from birth. The combination of an mGluR5 antagonist and GSK3 inhibitors was not additive. Instead, it was discovered that mGluR5 signaling and GSK3 activation in the FX mouse are coordinately elevated, with inhibition of mGluR5 leading to inhibition of GSK3. These findings raise the possibility that GSK3 is a fundamental and central component of FXS pathology, with a substantial treatment potential.
Min
Wenzhong William
WW
St. Luke's-Roosevelt Institute for Health Sciences, Columbia University, 432 W. 58th St., Rm. 411, New York, NY 10019, USA.
Yuskaitis
Christopher J
CJ
Yan
Qijiang
Q
Sikorski
Christopher
C
Chen
Shengqiang
S
Jope
Richard S
RS
Bauchwitz
Robert P
RP
D000161:Acoustic Stimulation / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002951:Citrates / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage; D018021:Lithium Chloride / Q000008:administration & dosage; D008297:Male; D008301:Maleimides / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D012694:Serine / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives
D018692:Antimanic Agents; D002951:Citrates; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D038362:Glycogen Synthase Kinase 3; D007211:Indoles; D018021:Lithium Chloride; D008301:Maleimides; D011725:Pyridines; D012694:Serine; D013844:Thiazoles; D014508:Urea; C497684:Fmr1 protein, mouse; C417521:SB 216763; C070669:lithium citrate; C121465:6-methyl-2-(phenylethynyl)pyridine; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea